Pharmacology of Diabetes

Type 1 DM – Insulin: acts by tyrosine kinase system → increases glucose uptake by muscles and fat, decreases hepatic glucose output, and controls postprandial hyperglycemia. Duration of action of an insulin preparation differed
from other insulin preparations mainly due to change in its rate of absorption from the site of injection.
Onset of Duration
Preparation Peak AE Interactions Uses Other
action of action
Rapid-acting (5-15 minutes before meal) -PK: SC, IM, IV. Site of injection: most rapid
-Hypoglycemia: -Type 1 DM
Insulin lispro --blockers (-1 selective & non-selective): from abdominal wall>arm>buttock>thigh.
palpitations, sweating,
Insulin aspart 10-30 min 30-60 min 3-5 hrs mask symptoms of hypoglycemia
anxiety, nausea, -Diabetic ketoacidosis
Insulin glulisine (palpitations, tremors, anxiety) -Rapid-acting & short-acting insulins used
hunger, headaches, (hyperglycemia, acidosis,
Short-acting (30 minutes before meal) for controlling post-prandial
confusion, dizziness, dehydration)
Regular insulin 30-60 min 1-2 hours 5-7 hrs -Ethanol: blocks gluconeogenesis & hyperglycemia
blurred vision, bizarre
Intermediate-acting behavior, seizures, glycogenolysis → precipitates hypoglycemia -Diabetes in pregnancy (drug of
NPH -Intermediate & long-acting insulins used to
1-2 hrs 6-12 hrs 18-24 hrs coma choice)
(Insulin isophane) provide basal levels in between meals.
-Salicylates
Long-acting Glargine has sustained “peak-less”
-Allergic reactions -Type 2 diabetics: who fail to respond
absorption → associated with less
-Loop diuretics & thiazides:  blood glucose to combination therapy with oral
hypoglycemia.
-Lipodystrophy levels &  effectiveness of insulin; antidiabetic agents; who have
Insulin glargine 1-2 hrs No Peak 24 hrs (atrophy or concomitant use with insulin →  risk of contraindications for using oral
-Regular insulin can be injected IV (used
Insulin detemir 1-2 hrs 3-9 hrs >12 hrs hypertrophy of fat hypokalemia → ventricular arrhythmia, antidiabetic drugs & exenatide; who
in diabetic ketoacidosis & hyperglycemic
tissue at site of respiratory paralysis, & death are under stressful conditions
emergencies)
injection) (surgery, acute illness, accident)

Type 2 DM
• Goal of all MOA’s:  sugar levels
• Diet and exercise is important in the initial management of Type 2 DM before starting treatment with oral antidiabetic agents.
Insulin Secretagogues (hypoglycemic effect requires functioning beta-cells in the pancreatic islets of Langerhans)
Half-life Duration of
Class Drug MOA Adverse Effects Interactions Uses
(hrs) action (hrs)
Tolbutamide* 4-5 6-12 Hypoglycemia (very rare); weight gain; safe in elderly
-Potentiation of hypoglycemic effect:
-Block ATP-sensitive K+ Hypoglycemia (more common); Disulfiram-like
reaction with alcohol; potentiate ADH action (water insulin, alcohol, -blockers, salicylates Management of
Chlorpropamide* channels in pancreatic 24-32 ~60 -Diminished hypoglycemic effect: neurogenic diabetes
beta cells → change retention) → dilutional hyponatremia → SIADH;
corticosteroids, thiazides, loop- insipidus
Sulfonylureas resting potential of cells weight gain
diuretics, phenytoin
Glyburide** → opening of voltage- 4-6 18-24 Hypoglycemia; weight gain
-CI: pregnancy. Sulfa allergy,
gated calcium channels Hypoglycemia (less chances); weight gain; preferred in
Glipizide** 2-4 14-16 significant hepatic and renal
→ calcium influx → elderly
insufficiency
Glimepiride** release of preformed 5-7 ~24 Hypoglycemia (less chances); weight gain
insulin. Short-duration
-Sulfonylureas reduce Control postprandial
(fast-acting: taken
Meglitinides Repaglinide glucagon concentrations <1 Hypoglycemia (less chances); weight gain hyperglycemia, allergic to
10-15mins before
sulfonylureas
meal)
** are preferred over * for managing Type 2 DM. 2nd generation agents are more potent, equally efficacious, and their biological actions last longer.

Class Drug MOA Adverse effects Uses

-GI disturbances: nausea, diarrhea -“Anti-hyperglycemic”
- Glucose production by the liver (acts mainly in the liver)
-Lactic acidosis: chances  in predisposing conditions – renal -For obese type 2 DM patients
-Activation of AMP-stimulated protein kinase →  gluconeogenesis,  insulin
Biguanides Metformin impairment, hepatic disease, alcoholism, cardiac failure, MI, & (reduce plasma triglycerides by
resistance,  glucose absorption from GI,  plasma glucagon 15-20%)
chronic hypoxic lung disease
-Half-life = 1.5-3hrs -Polycystic ovary syndrome
-Does not cause hypoglycemia or weight gain
- Uptake of sugar by muscle & fat cells
Rosiglitazone
-Selective agonist of nuclear PPAR - activation of insulin-responsive genes that -Fluid retention, edema, angina, MI, heptatoxicity
Thiazolidinediones regulate carbohydrate & lipid metabolism →  insulin resistance /  insulin -Do not cause hypoglycemia “Insulin sensitizers”
Pioglitazone sensitivity (activation of adiponectin) -CI: congestive heart failure (BBW) & liver disease
-Max effects after 6-12wks
 -Slow sugar absorption in the gut
Acarbose -Flatulence, diarrhea, abdominal pain
-Glucosidase -Inhibit breakdown of starch & oligosaccharides to monosaccharaides by
-Hypoglycemia when used with other secretagogues (Tx: glucose)
inhibitors inhibiting -glucosidases → slows absorption of carbohydrates & blunts
Miglitol -CI: inflammatory bowel disease, renal & hepatic dysfunction
postprandial rise in plasma glucose
-“Glucose-dependent” insulin secretion ( insulin secretion when glucose levels
GLP-1 receptor are elevated)
-Nausea, vomiting, diarrhea
agonist (incretin Exenatide -Suppresses glucagon secretion
-Rare & fatal: necrotizing & hemorrhagic pancreatitis -SC
mimetic) -Slows gastric emptying ( rate of glucose entering circulation)
- Appetite
- Degradation of endogenous incretins →  GLP-1 & GIP
DPP-4 inhibitor Sitagliptin Nasopharyngitis, upper respiratory infections, headache
- Glucose mediated insulin secretion &  glucagon levels